The phenotypic effect of some single nucleotide polymorphisms (SNPs) depends on their parental origin. We present a novel approach to detect parent-of-origin effects (POEs) in genome-wide genotype data of unrelated individuals. The method exploits increased phenotypic variance in the heterozygous genotype group relative to the homozygous groups. We applied the method to >56,000 unrelated individuals to search for POEs influencing body mass index (BMI). Six lead SNPs were carried forward for replication in five family-based studies (of ∼4,000 trios). Two SNPs replicated: the paternal rs2471083-C allele (located near the imprinted KCNK9 gene) and the paternal rs3091869-T allele (located near the SLC2A10 gene) increased BMI equally (beta = 0.11 (SD), P<0.0027) compared to the respective maternal alleles. Real-time PCR experiments of lymphoblastoid cell lines from the CEPH families showed that expression of both genes was dependent on parental origin of the SNPs alleles (P<0.01). Our scheme opens new opportunities to exploit GWAS data of unrelated individuals to identify POEs and demonstrates that they play an important role in adult obesity.

Original publication

DOI

10.1371/journal.pgen.1004508

Type

Journal article

Journal

PLoS genetics

Publication Date

31/07/2014

Volume

10

Addresses

Department of Genomics of Common Disease, Imperial College London, London, United Kingdom.

Keywords

Generation Scotland Consortium, LifeLines Cohort study, GIANT Consortium, Humans, Obesity, Genetic Predisposition to Disease, Potassium Channels, Tandem Pore Domain, Body Mass Index, Gene Expression Regulation, Genomic Imprinting, Genotype, Polymorphism, Single Nucleotide, Adult, European Continental Ancestry Group, Female, Male, Glucose Transport Proteins, Facilitative, Genome-Wide Association Study